For many metastatic solid tumors such as melanoma, the primary treatment modality continues to be cytotoxic chemotherapy, which is often minimally effective. Adoptive T-cell therapy (ACT) has re-emerged as a promising cancer treatment modality that demonstrates curative potential and may have the capacity for broad application. The rationale to apply ACT for the treatment of tumors is predicated on the observation that lymphocytic infiltrates are present within the tumor environment, and their presence correlates highly with improved outcome. These infiltrates consist mostly of CD4+ and CD8+ T cells. The anti-tumor activity of these cells is well-illustrated by animal studies and positive clinical outcome of adoptive transfer of ex-vivo expanded tumor-infiltrating lymphocytes (TILs) in the treatment of metastatic melanoma. Several studies show that the number of infused CD8+ T cells strongly correlates with response to treatment, suggesting an important role for MHC class I restricted, cytotoxic T cell (CTL) mediated tumor killing. Melanoma is an aggressive cancer derived from melanocytes, the pigment-generating cells of the skin. Malignant melanoma is responsible for ~60% of deaths from skin cancers, and both incidence and prevalence of this disease have increased over the past few decades. Based on the American Cancer Society's projections, in the United States for 2014, an estimated 76,100 new cases of malignant melanoma will be diagnosed (~43,890 in men and 32,210 in women) with a projection of 9,710 deaths (~6,470 men and 3.240 women). Our published and preliminary results show for the first time that: 1) cbx-3/HP-1? controls the effector capacity of CD8+ T cells mainly the production of perforin and interferon (IFN)-?; 2) cbx-3/HP-1? is recruited to Prf1 (gene encoding perforin) and Ifng (gene encoding INF-?) loci where it maintains a chromatin structure that limits Runx3 and Pol II binding; 3) cbx-3/HP-1? deficiency enhances anti-tumor immunity in mice implanted with B16 melanoma cells. Thus we propose the following hypothesis: the enhanced tumor killing activity observed in cbx-3/HP-1? deficient mice is conferred by TILs, specifically CD8+ T cells. Adoptive T-cell therapy using cbx-3/HP-1? deficient CD8+ T cells will protect mice against metastatic solid tumors. We will use the well-established B16 melanoma mouse model as a proof of concept, and the following aims form the core of our proposal. Our goals are: 1) show that cbx-3/HP-1? deficient TILs protect mice against melanoma (Aim 1); 2) Show that ACT with cbx-3/HP-1? deficient CD8+ T cells protects mice against metastatic solid tumors (Aim 2). The successful completion of our proposal will provide clinician-scientists in the cancer research community with insights to translate our discovery into innovative treatment modalities for melanoma as well as other metastatic solid tumors for with ACT is beginning to show promise.